Antigenic variation in human immunodeficiency virus type 1 (HIV-1) stands in the way of a broadly effective vaccine candidate. Understanding the specific sites in the HIV-1 envelope which confer escape from humoral immunity if localized and conserved in nature would allow for the construction of a better immunogen. Ongoing studies have now defined two positions in gp41 (662, 668) which act in concert to allow V3-specific and gp120-CD4-specific antibodies from effectively neutralizing HIV-1 in vitro. Similar efforts to identify conserved epitopes on HIV-I gp12O/41 were studied by fractionization of a natural HIV-1(+) polyclonal response by idiotypes specific for V3 and gp120/CD4 binding antibodies. No completely conserved epitopes were discovered between divergent laboratory strains of HIV-1. Cross-reactivity of V3-specific antibodies and a new non-V3 neutralizing epitope which increases its availability to antibody after binding to CD4 was observed. Further immunological analysis of the humoral response to HIV-1 has demonstrated a restricted and dominant antibody population made to functional epitopes, suggesting an abnormality in the B cell response to the virus during natural infection. Alpha- interferon has been demonstrated to provide an antiviral effect in vitro; however, the mechanisms are not well understood. Recent studies suggest that alpha-interferon imposes a molecular defect in the assembly of gp120/41 onto the virion. It was also noted that "tropism", as has been discussed so actively in the field, does not appear to exist when one is talking about field isolates or strains in peripheral blood mononuclear cells and primary macrophages.